The long-term objective of this proposal is to develop effective antimicrobial peptides as a new therapeutic modality for the treatment of acne. The increase in antibiotic-resistant strains of Propionibacterium acnes, the bacterium that contributes to the pathogenesis of acne, has hastened research for development of novel therapeutic agents. We hypothesize that the body's own natural antimicrobial peptides may be useful therapeutic agents in the treatment of acne. Our preliminary data indicate that the human-derived antimicrobial protein granulysin appears in acne lesions during the resolution phase, is effective at killing P. acnes and blocks P. acnes-induced monocyte cytokine release. We propose experiments to study the antimicrobial and antiinflammatory activity of granulysin-derived peptides, and predict their efficacy as toprincipal investigatorcal agents in the treatment of acne. Our specific aims are to 1) identify and engineer antimicrobial peptides that are effective at killing P. acnes, 2) identify peptides that have anti-inflammatory properties since peptides that have both antimicrobial activity and anti-inflammatory properties would be ideal therapeutic candidates, and, 3) determine the ability of granulysin-derived peptides to penetrate skin and microcomedones. These studies will have the potential to develop a new class of antibiotic compounds for use in the treatment of cutaneous infections ncluding acne vulgaris as well as other skin infections in which bacteria are involved.